Ambrisentan is an endothelin receptor antagonist used in the therapy of pulmonary arterial hypertension (PAH). Ambrisentan has been associated with a low rate of serum enzyme elevations during therapy, but has yet to be implicated in cases of clinically apparent acute liver injury.

Ambrisentan was first approved by the U.S. Food and Drug Administration (FDA) on Jun 15, 2007, then approved by the European Medicines Agency (EMA) on Apr 21, 2008 and approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on Jul 23, 2010. In 2000, Abbott, originator of ambrisentan, granted Myogen (acquired by Gilead in 2006) a license to the compound for the treatment of PAH. In 2006, GlaxoSmithKline obtained worldwide rights to market the compound for PAH worldwide, with the exception of the U.S. It is marketed as Letairis® by Gilead in US.

Ambrisentan is an endothelin receptor antagonist, and is selective for the type A endothelin receptor (ETA). It is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise ability and delay clinical worsening. Studies establishing effectiveness included predominantly patients with WHO Functional Class II-III symptoms and etiologies of idiopathic or heritable PAH (64%) or PAH associated with connective tissue diseases (32%).

Letairis® is available as film-coated tablet for oral use, containing 5 or 10 mg of free Ambrisentan. The recommended starting dose is 5 mg once daily with or without food, and increase the dose to 10 mg once daily if 5 mg is tolerated.

Introduction to Endothelin

Endothelin (ET) derived from vascular endothelial cells (ECs), which consists of a 21 amino acid peptide, has a strong and persistent vasoconstrictive action (1). ET has three family peptides (ET-1, ET-2, and ET-3). As the distribution and properties of these peptides are different, each peptide is believed to play specific physiological roles. ET has two types of receptor: the ETA receptor with a high affinity for ET-1 and ET-2 is mainly located on muscle cells, whereas the ETB receptor with an affinity for all three peptides lies on endothelial, epithelial, endocrine, and nerve cells. Of the three ET isoforms,

ET-1 plays a much more important role in the regulation of vascular tone than the others and has a powerful effect on the cardiovascular system. Thus, the role of ET-1 and its receptors as the etiology or precipitating factors in various cardiovascular diseases (CVD) has been investigated (2, 3). In addition, numerous studies have reported effective treatment targeted at ET-1 in pulmonary hypertension, salt-sensitive hypertension, diabetes, and acute and chronic kidney diseases using ETconverting enzyme (ECE) inhibitors and ET-receptor antagonists (2, 4). Several animal models genetically lacking ET-1 and ET receptors have also been used as a tool for determining the physiological and pathophysiological roles of ET-1 and ET receptors in CVD (5 – 10).

Introduction to the ET system

Endothelial Cells (ECs) are known as the main physiological source of vascular ET-1. Vascular smooth muscle cells (VSMCs), macrophages, leukocytes, cardiomyocytes, and fibroblasts are also capable of ET-1 production (11 – 13).

Several studies have indicated that various physical and chemical factors such as thrombin, angiotensin II, cytokines, hypoxia, and shear stress stimulate ET-1 gene expression in ECs by DNA binding of transcription factors including activator protein-1, GATA-2, Smad, nuclear factor-kappa B (NF-κB), and hypoxia inducible factor-1 (14 – 18). On the other hand, ET-1 is synthesized as an inactive 203-amino-acid precursor, preproET-1, which is proteolytically cleaved to yield a second inactive 39 (or 38)-amino-acid segment called ‘big’ ET-1.

The last part of the proteolytic process is mainly carried out by ECE (ECE-1 and ECE-2) and leads to the production of the bioactive form of 21-amino-acid peptide ET-1. As ET-1 release from ECs is constitutive, ET-1 biosynthesis and release appear to be mainly controlled via regulation of gene transcription and/or ECE activity.

On the other hand, although another ETB-receptor subtype (ETB2) located on VSMCs exerts vasoconstriction, it has become clear that ETB2 receptor–induced vasoconstriction is negligible under normal conditions but becomes more important in some kinds of diseases such as atherosclerosis and essential hypertension (24 – 26).

Has the considerable promise of ET-1 manipulation as a therapeutic option been realized? Its release, perhaps from a dysfunctional endothelium, could have a major role in the pathogenesis of a variety of cardiovascular diseases (reviewed by Haynes and Webb, 1992 andRubanyi and Polokoff, 1994). The discovery of endothelin-1 (ET-1) almost 20 years ago (Yanagisawa et al., 1988) was rapidly followed by prospects that pharmacological manipulation of the ET-1 system might provide powerful new treatments for many clinically significant cardiovascular conditions.

Fig. 2.

Proposed explanation for the interaction between the ET-1 system and norepinephrine (NE) release from cardiac sympathetic nerve endings in protracted myocardial ischemia. ATP is depleted and axoplasmic pH is reduced under ischemic conditions.This diminishes vesicular storage of NE, leading to a large increase in free axoplasmic NE. Compensatory activation of the neuronal Na+/H+ exchanger (NHE) by axoplasmic acidification causes influx of Na+ in exchange for H+. The resulting Na+ accumulation triggers a massive release of free axoplasmic NE via a reversal of the NE transporter (NET). Released NE acts on postsynaptic adrenoceptors on myocytes. Stimulation of the ETA receptor existing in sympathetic nerve endings by endogenously generated or exogenously applied ET-1 enhances neuronal NHE activity and results in increases in NE release. In contrast, exogenously applied big ET-1 is converted to ET-1 by ECE-1 expressed on the cell surface, and this ET-1 preferentially binds to the ETB receptor located on NOS-containing cells. As a result, increments in NO production cause inhibition of NE release. NCX: Na+/Ca2+ exchanger, VMAT: vesicular monoamine transporter.

Over 200 references in this paper trace the trail of experiments and clinical trials conducted by induction of therapeutic potential compounds that target the ET system. The role of ET-1 in cardiovascular disease and development of pharmacological tools that manipulate its activity, include agents that

The rapid identification of such compounds led remarkably quickly to the development of orally active antagonists (Clozel et al., 1994) and their administration to patients (Kiowski et al., 1995). Additional insight into ET physiology has been gained from studies with

for treatment of PAH is the most obvious demonstration of the clinical benefit derived from therapeutic manipulation of the ET-1 system in cardiovascular disease. This development of one of the first effective treatments for a condition with poor prognosis has obvious clinical significance and is likely to be extended to include PAH associated with connective tissue disorders.

Thus, ET antagonists are already realizing their potential in treatment of cardiovascular diseases, while early clinical data suggest these compounds may prove beneficial in other conditions, such as resistant hypertension,chronic kidney disease and SAH. In contrast, a potential role in conditions associated with vascular remodelling (restenosis, chronic obstructive pulmonary disease and transplant graft rejection) remains speculative and requires further investigation. It should also be noted that the clinical experience with ET antagonists in patients with cardiovascular disease remains relatively limited and the design of new trials could be improved using knowledge gained from previous studies, particularly with regard to drug dose and selectivity. These successes must obviously be balanced against the failure of ET antagonists to realize their potential in the treatment of heart failure, and the fact that teratogenic effects have restricted their possible use to treatment of conditions where childbearing potential is unlikely to be an issue.

Several reasons have been proposed to account for the disappointing outcomes in clinical trials as compared to investigations using animal models of disease, including

inadequate models or a bias in publication towards positive outcomes;

incorrect dose/timing of administration;

the need to show additional benefit over existing treatments; and

ET activation being a consequence rather than a cause of the condition.

Whatever the reason, this experience urges caution in extrapolating data obtained in vitro and in animals to humans. It is hoped that additional information will emerge from unpublished clinical trials that will shed light on previous failures (Kelland and Webb, 2006), and that the combination of powerful pharmacological and molecular approaches will help us to better understand the role of ETA and ETB receptors in health and diseaseso as to fully realize the clinical potential created by the identification of the powerful vasoconstrictor peptide, ET-1.

Further studies have addressed the role of ET receptor antagonism in erectile dysfunction and aneurysmal SAH, with mixed results. A double-blind pilot study of 53 patients with mild-to-moderate erectile dysfunction demonstrated no benefit of the ETA-selective antagonist BMS-193884 (100mg by mouth) over placebo (Kim et al., 2002).

The ETA-selective antagonist clazosentan was specifically designed for intravenous use in conditions characterized by cerebral vasoconstriction. Its potential in treating severe aneurysmal SAH has recently been addressed in a phase IIa pilot study for the Clazosentan to Overcome Neurological iSChaemia and Infarction OccUrring after Sub-arachnoid haemorrhage (CONSCIOUS-1) trial (Vajkoczy et al., 2005). This ‘pre-CONSCIOUS-1′ study documented a reduction in the frequency and severity of cerebral vasospasm following SAH.

There is considerable evidence that the potent vasoconstrictor endothelin-1 (ET-1) contributes to the pathogenesis of a variety of cardiovascular diseases. As such, pharmacological manipulation of the ET system might represent a promising therapeutic goal. Many clinical trials have assessed the potential of ET receptor antagonists in cardiovascular disease, the most positive of which have resulted in the licensing of the mixed ET receptor antagonist bosentan, and the selective ETA receptor antagonists, sitaxsentan and ambrisentan, for the treatment of pulmonary arterial hypertension (PAH).

In contrast, despite encouraging data from in vitro and animal studies, outcomes in human heart failure have been disappointing, perhaps illustrating the risk of extrapolating preclinical work to man. Many further potential applications of these compounds, including

resistant hypertension,

chronic kidney disease,

connective tissue disease and

sub-arachnoid haemorrhage

are currently being investigated in the clinic. Furthermore, experience from previous studies should enable improved trial design and scope remains for development of improved compounds and alternative therapeutic strategies.

Although ET-converting enzyme inhibitors may represent one such alternative, there have been relatively few suitable compounds developed, and consequently, clinical experience with these agents remains extremely limited. Recent advances, together with an increased understanding of the biology of the ET system provided by improved experimental tools (including cell-specific transgenic deletion of ET receptors), should allow further targeting of clinical trials to diseases in which ET is involved and allow the therapeutic potential for targeting the ET system in cardiovascular disease to be fully realized.

Figure 3

Generation and action of endothelin-1 (ET-1) in the vascular wall. The 21-amino-acid peptide, ET-1, is the eventual product of a gene on chromosome 6 that encodes preproET-1 protein. This is converted to proET-1 on secretion into the cytoplasm, which Endothelin-1 is generated from precursor peptides via a two-step proteolytic pathway. Transcription of a gene on chromosome 6 generates mRNA encoding the 212-amino-acid peptide, preproET-1, which, once translated, is stripped of its signal sequence and secreted into the cytoplasm as proET-1 (Inoue et al., 1989). ProET-1 is further cleaved by a furin-like endopeptidase to the 38-amino-acid precursor molecule big ET-1, which circulates in plasma at low concentration but is not thought to possess significant bioactivity (Yanagisawa et al., 1988). Removal of a further 17 COOH-terminal residues, classically but not exclusively by ET-converting enzymes (ECE), results in formation of the mature 21-amino-acid ET-1 (Hirata et al., 1990).

The STATE OF SCIENCE for the ET System has been UPDATED by a 2012 study published by the Japanese Pharmacological Society in the Journal of Pharmacological Sciences, 2012.

Since the discovery of ET-1, many researchers have elucidated the physiological and pathophysiological role of ET-1 and ET receptors in the cardiovascular system over the past 20 years. Among many non-peptide and orally available ET-receptor antagonists developed so far, the nonselective ETA/ETB-receptor antagonist bosentan and selective ETA-receptor antagonist ambrisentan are now clinically utilized as agents for pulmonary artery hypertension. There is a possibility that ambrisentan could be widely used in the treatment of pulmonary hypertension because of less interactions with other drugs or side effects such as liver dysfunction. In addition, future clinical applications may provide new findings about which antagonist is more effective, a nonselective ETA/ ETB-receptor or selective ETA-receptor antagonist.

On the other hand, although the selective ETA-receptor antagonist sitaxsentan, which was released in Europe and the United States, was recently forced to be withdrawn because of a high risk of liver failure, it is hoped in the future that other ET-receptor antagonists, including macitentan and zibotentan, currently being developed can be utilized in clinical treatment targeted at the cardiovascular ET-1 system.

In Pathophysiological Roles of Endothelin Receptors in Cardiovascular Diseases

Endothelin (ET)-1 derived from endothelial cells has a much more important role in cardiovascular system regulation than the ET-2 and ET-3 isoforms. Numerous lines of evidence indicate that ET-1 possesses a number of biological activities leading to cardiovascular diseases (CVD) including hypertension and atherosclerosis.Physiological and pathophysiological responses to ET-1 in various tissues are mediated by interactions with ETA- and ETB-receptor subtypes. Both subtypes on vascular smooth muscle cells mediate vasoconstriction, whereas the ETB-receptor subtype on endothelial cells contributes to vasodilatation and ET-1 clearance. Although selective ETA- or nonselective ETA/ETB-receptor antagonisms have been assumed as potential strategies for the treatment of several CVD based on clinical and animal experiments, it remains unclear which antagonisms are suitable for individuals with CVD because upregulation of the nitric oxide system via the ETB receptor is responsible for vasoprotective effects such as vasodilatation and anti-cell proliferation. In this review, we have summarized the current understanding regarding the role of ET receptors, especially the ETB receptor, in CVD.

POINT # 2:

The downstream effects of ET-1 are mediated by two G-protein-coupled receptors ETA and ETB. In the vasculature, the

Stimulation of the ETB1 receptor leads to the release of vasodilators such as

nitric oxide (NO) and

prostaglandin I2 and

clearance of ET-1 from the circulation within the lungs, kidneys, and liver (19 – 23).

Many vascular relaxing or contraction factors produced in the blood vessel wall maintain normal endothelial function by mutually antagonistic actions. In particular, there are various reports regarding the interaction of ET-1 and NO (27). For instance, ET-1 binding to the ETB1 receptor leads to phosphoinositide 3-kinase (PI3K) activation and subsequent production of phosphatidylinositol- 3,4,5-trisphosphate, which results in recruitment and activation of protein kinase B / Akt (28). This PI3K/Akt pathway is responsible for the phosphorylation and activation of endothelial NO synthase (eNOS). On the other hand, ET-1 also reduces eNOS expression and its activity through increases in hydrogen peroxide by the ETA receptor (29). Therefore, reduced ETB-receptor function and/or overactivation of the ETA receptor eliminate the protective function by NO in vessels and promote the pathological formation of various circulatory diseases

POINT # 3:

3.1 Activation of PKC

Locally generated ET-1 contributes to tissue repair or remodeling of the infarcted heart in an autocrine/paracrine manner, thereby exerting an immediate beneficial effect on damaged tissue (33, 34). Other studies reported that ET-1 administered prior to the onset of ischemia exhibited cardioprotective effects (35, 36). Exogenous ET-1 mimics the cardioprotective effect of pre-conditioning against infarction, apparently via ETA receptor– mediated activation of PKC and a mitochondrial type of ATP-sensitive K+ channel (37, 38). On the other hand, a substantial and long lasting rise in ET-1 induces myocardial hypertrophy, which is associated with a maladaptive effect on myocardial structure and function, thereby leading to fatal events (39 – 42).

On the other hand, both pharmacological blockade and genetic deficiency of ETB receptors exaggerated the post-ischemic excessive NE release and cardiac dysfunction. Oikonomidis et al. demonstrated that NE levels during the early phase of myocardial infarction are much higher in ETB-deficient rats than wild-type rats and this contributes to the incidence of ventricular arrhythmogenesis, thereby suggesting that the ETB receptor exerts a suppressive effect in sympathetic hyperactivity during the early phase of myocardial infarction (48). Furthermore, activation of the ETB receptor with sarafotoxin-6c substantially

reduced NE release,

myocardial infarct size, and

ischemic arrhythmias (47, 49).

3.3 Big ET-1 must be converted to ET-1 and exerts similar physiological functions

Big ET-1 exerts several physiological actions similar to ET-1, but it must be converted to ET-1 via enzymatic degradation by ECE (50). ECE expression and its enzyme activities are increased in myocardial infarction (51), thereby suggesting that a selective ECE inhibitor may be useful in ischemic cardiac diseases at the clinical level, which warrants further attention. In fact, SM-19712 and FR901533, both of which are highly selective ECE inhibitors, exert a desirable influence on myocardial infarction by decreasing plasma concentrations of ET-1 (52, 53).

On the other hand, exogenously applied big ET-1 has qualitatively similar effects to ET-1 in the cardiovascular system in vivo and in vitro (54 – 57). Against this background, Sharif et al. demonstrated that exogenously applied ET-1 exhibited opposite effects to endogenously released ET-1 on ischemic ventricular arrhythmias (58).

The Japanese Team also reported that exogenous big ET-1 suppressed ischemia/reperfusion-induced NE overflow and improved cardiac dysfunction observed after reperfusion, in spite of the fact that ET-1 content in coronary effluent from the heart exposed to ischemia/reperfusion was increased by exogenous big ET-1 application (59). In addition, treatment with big ET-1 in the presence of A-192621, a selective ETB-receptor antagonist, failed to exert beneficial effects against ischemia/reperfusion-induced NE overflow and subsequent cardiac dysfunction. Thus, ET-1 generated from exogenously applied big ET-1 preferentially may act on ETB receptors rather than ETA receptors, leading to an increase in NO production and subsequent suppression of NE overflow.

POINT # 4:

Neointimal Formaion and Baloon Angioplasty Intervention

Cardiovascular hypertrophy and remodeling are not simply a response to elevated blood pressure. Various vasoactive substances, such as angiotensin II, are implicated in the development of these structural changes (72). ET-1 has potent mitogenic and hypertrophic properties, mainly via stimulation of ETA receptors (73). ETB receptor– mediated actions also protect against cardiovascular hypertrophy via endothelial NO generation, which inhibits mitogenesis and the proliferation of VSMCs (74).

Balloon angioplasty and stent insertion are now widely used for the treatment of coronary arterial disease. Although these procedures improve regional myocardial blood flow by dilating stenotic coronary vessels, one major drawback of this therapeutic approach is restenosis after the procedure because of the proliferation of VSMCs and neointimal formation triggered by mechanical damage to ECs. Several growth factors or vasoactive peptides are related to the process of neointimal formation. In a clinical study, expressions of ECE, ET-1, and ET receptors were enhanced in neointimal VSMCs after percutaneous coronary intervention in human coronary arteries (75). In addition, increases in ET-1 levels were observed in the coronary circulation after percutaneous transluminal coronary angioplasty (76). Anggrahini et al. recently demonstrated that ET-1 derived from ECs mainly contributes to the process of vascular remodeling in the model of flow cessation (10). Thus, ET-1 is closely related to the pathogenesis of restenosis after angioplasty. Similar results have been reported in animal models with restenosis such as balloon injury (77, 78).

Murakoshi et al. showed that vascular remodeling caused by the cessation of blood flow was markedly accelerated in the carotid artery of ETB receptor–knockout mice, and long-term treatment with an ETB-receptor antagonist worsened vascular remodeling in wild-type mice (6).

In contrast, selective ETA-receptor blockade could attenuate this vascular remodeling in the same animals. There has also been a report showing that ET-1 contributes to the remodeling of mesenteric resistance arteries in diabetes via activation of ETA receptors, and ETB receptor–mediated actions provide vasoprotective effects (79). Our previous report has demonstrated that vascular remodeling is markedly attenuated by treatment with a selective ETA receptor antagonist, whereas pharmacological blockade of ETB receptors aggravates neointimal hyperplasia after balloon injury (80). Treatment with an ETA/ETB dual receptor antagonist also suppresses neointimal hyperplasia and the efficacy of treatment is comparable with that of a selective ETA-receptor antagonist (80), thereby suggesting that the antagonism of ETB receptors does not seem to impair the positive effects of concomitant ETA receptor antagonism. Furthermore, we also confirmed similar results in ETB-deficient rats. Therefore, antagonism of the ET-1 / ETA receptor pathway appears to be essential for preventing neointimal hyperplasia after balloon injury, irrespective of the presence of ETB receptor–mediated actions.

POINT # 5:

Pulmonary Hypertention

The lungs are known to synthesize ET-1 and possess ETA and ETB receptors, both of which are involved in physiological and pathophysiological actions of ET-1 in the lung. In particular, endothelial ETB receptors in lungs are responsible for circulating ET-1 clearance, with close to 50% removal during pulmonary transit in humans (81).

These findings suggest that an ETA/ETB-receptor antagonist brings reasonable validity by suppressing overactivation of the ET-1 / ETA receptor system and vasoconstriction via the ETB2 receptor. Moreover, it is less likely that the ETB1 receptor actively functions as a protective factor through increases in NO production.

POINT # 6:

Hypertension: Salt-sensitive type

ETB receptor–mediated actions are protective in the pathogenesis of salt-sensitive hypertension. These results also suggest that the antagonism of the ETA receptor is essential for protection from cardiovascular disease including salt-sensitive hypertension, irrespective of the presence of the ETB receptor. This view may explain the findings that selective ETA-receptor antagonists and nonselective ETA/ETB-receptor antagonists similarly improve salt-sensitive hypertension and related tissue injuries.

POINT # 7:

Gender Differences in CVD

ETB receptor–mediated actions seem to occur downstream of the vasoprotective effects of estrogen, although the relationship between ETB receptor– and estrogen receptor– signaling systems remains unclear. On the other hand, neointimal hyperplasia observed in female ETB deficient rats is almost completely suppressed by ETA or ETA/ETB-receptor antagonists. Thus, augmentation of ETA receptor–mediated actions under ETB-receptor dysfunction seems to be responsible for the abolition of sex differences in vascular remodeling.

Sex differences are considered to be caused by the vasoprotective effect of estrogen (108 – 110). In fact, several clinical studies showed that postmenopausal women who receive estrogen replacement therapy (ERT) have a substantially lower risk of incidence of cardiovascular disease (111, 112). The protective effect of estrogen on the cardiovascular system is closely related to the up-regulation of endothelial NO production and downregulation of adhesion molecule activity, smooth muscle proliferation/migration, and superoxide production (113 – 115).

It is reasonable to assume that 17β-estradiol is mainly involved in sex differences in the ET system. Sex differences in ET-receptor density, as well as in the ratio of ET-receptor subtypes, have been also investigated. Ergul et al. reported that men’s saphenous veins have a larger number of ET receptors and an increased ratio of ETA to ETB receptors compared to women’s saphenous veins and that these differences were reflected by the sex differences in ET-1-induced vascular contractile responses (127). On the other hand, although several animal studies also indicated that ET receptors are involved

in the sex differences in the incidence of CVD, the effect of estrogen on these receptors is quite contradictory.

For example, Nuedling et al. demonstrated upregulation of the ETB receptor in the heart of ovariectomized female spontaneously hypertensive rats, which could be reversed by exogenous estrogen replacement (128). They also confirmed downregulation of the ETB receptor by 17β-estradiol in cultured cardiomyocytes. Others reported similar results showing that vascular mRNA expression of ETB, but not ETA receptors in DOCA-salt–induced hypertensive rats was higher in males than that observed in females (129, 130).

Table 1

Comparison of ECE inhibitors in clinical development and experimental use

aWhere stated, the ECE isoform referred to is ECE-1. Selectivity ratios are displayed to two significant figures. Blank spaces indicate that we were unable to locate appropriate values in the literature.

bAvosentan has also has been described as an ETA-selective antagonist but this is, at best, debatable, given the published data. Selectivity ratios are displayed to two significant figures. Blank spaces indicate that we were unable to locate appropriate values in the literature.

Abstract

Endothelin-1 (ET-1) is involved in norepinephrine (NE) overflow and cardiac dysfunction after myocardial ischemia/reperfusion via the activation of ETA receptors. As ET-1 is generated from big ET-1 via endothelin-converting enzyme (ECE), ischemia/reperfusion-induced cardiac injury may be exacerbated by exogenous big ET-1. The aim of this study was to investigate the influence of exogenously applied big ET-1 on ischemia/reperfusion-induced NE overflow and cardiac dysfunction. According to the Langendorff technique, isolated rat hearts were subjected to 40-min global ischemia followed by 30-min reperfusion. Exogenous big ET-1 (0.1, 0.3 and 1 nM) was perfused, beginning 15 min before ischemia. Unexpectedly, higher doses (0.3 and 1 nM) of big ET-1 significantly improved indices of left ventricular function after ischemia/reperfusion, such as left ventricular developed pressure (LVDP), the maximum value of the first derivative of left ventricular pressure (dP/dtmax) and left ventricular end diastolic pressure (LVEDP). In addition, big ET-1 significantly suppressed excessive NE overflow in the coronary effluent from the postischemic heart. These effects of big ET-1 were markedly attenuated by treatment with SM-19712 (selective ECE inhibitor) or A-192621 (selective ETB receptor antagonist). On the other hand, those were not potentiated even though combined with ABT-627 (selective ETAreceptor antagonist). From these findings, we suggest that exogenous big ET-1 has beneficial effects on ischemia/reperfusion-induced cardiac injury. It seems likely that big ET-1 is converted to ET-1, locally in the heart, and this ET-1 preferentially binds to ETB receptors to exert its related beneficial actions.

Source

The first objective of the study was to compare the levels of big endothelin and endothelin-1 and other noninvasive parameters used for evaluation of disease severity in patients with stable chronic heart failure (CHF). Endothelin-1 and big endothelin plasma concentrations were measured in 124 chronic heart failure patients. The second objective of the study was to prove an association between endothelin-1 and big endothelin plasma levels and two frequent polymorphisms in the endothelin-1 coding gene (6p21-23) -3A/-4A and G (8002) A in patients with chronic heart failure. Thirdly, we tried to associate other noninvasive parameters of CHF, especially cardiothoracic index (CTI), NYHA classification, signs of pulmonary congestion (PC) and ejection fraction (EF) with determined genotypes of the two ET-1 polymorphic variants. There were significant differences between big endothelin levels in NYHA II versus IV (P<0.001) and NYHA III versus IV (P<0.001) and endothelin-1 in NYHA II versus IV (P<0.001) and NYHA III versus IV (P<0.001). No associations between plasma levels of endothelin-1 and big endothelin and polymorphisms G (8002) A and -3A/-4A in gene coding endothelin-1 were found. In patients with CHF with CTI above 60% the number of carriers of genotypes with ET-1 8002A (AA and AG genotypes) increases. Concerning on the -3A/-4A ET-1 polymorphism, we observed a significant difference in genotype distribution as well as in allelic frequency in the group of patients with CTI above 60% between patients without and with pulmonary congestion. The allelic frequency of 3A allele is twice elevated in the patients with pulmonary congestion (37.8 vs. 78.1%, respectively).

An Investigation of the Potential of circulating Endothelial Progenitor Cells (cEPCs) as a Therapeutic Target for Pharmacological Therapy Design for Cardiovascular Risk Reduction: A New Multimarker Biomarker Discovery

Dr. Larry,
Thank you for your comment. It is based on two SEMINAL papers in the UK, 2008 and in Japan 2012. I am the curator who wrote about ET in 2006, as per the references on ET on this Scientific Web Site.